The immune system can respond in two ways when exposed to an antigen. A positive response leads to differentiation of T and B cells, antibody production and to immunologic memory. A negative response leads to suppression or inactivation of specific lymphocytes and to tolerance. Tolerance can be defined as the failure of an organism to mount an immune response against a specific antigen. Normally, an organism is tolerant of its own antigens.
Autoimmune diseases are thought to result from an uncontrolled immune response directed against self antigens. In patients with multiple sclerosis (MS), for example, there is evidence that this attack is against the white matter of the central nervous system and more particularly to white matter proteins. Ultimately, the myelin sheath surrounding the axons is destroyed. This can result in paralysis, sensory deficits and visual problems. MS is characterized by a T cell and macrophage infiltrate in the brain. Autoreactive myelin-specific T cells have been isolated from MS patients, although T cells of the same specificity have been detected in normal individuals. J. M. LaSalle et al., J. Immunol. 147:774-780 (1991), J. M. LaSalle et al., J. Exp. Med. 176:177-186 (1992), J. Correale et al., Neurology. 45:1370-1378 (1995). Presently, the myelin proteins thought to be the target of an immune response in MS include myelin basic protein (MBP), proteolipid protein (PLP), and myelin-oligodendrocyte glycoprotein (MOG). Individuals who do not mount an autoimmune response to self proteins are thought to have control over these responses and are believed to be "tolerant" of self antigens. The evidence, therefore, that MS is caused by pathogenic T cells is necessarily indirect, but the close resemblance which the characteristics of this disease bear to those of the murine model, experimental autoimmune encephalomyelitis (EAE), suggest that MS is indeed caused by an aberrant immune response mediated by T cells.
The EAE mouse model for MS, the subject of intense and fruitful study for several years, displays many of the same histopathological and clinical characteristics as the relapsing remitting forms of MS. The T Lymphocyte in Experimental Allergic Encephalomyelitis, Ann. Rev. Immunol. 8:579-621 (1990). EAE can be induced in SJL mice by injection of mouse spinal cord homogenate (MSCH), MBP, PLP, by the injection of synthetic peptides whose sequences correspond to the major encephalogenic epitopes of myelin basic protein, MBP 84-104, proteolipid protein, PLP 139-151, or by adoptive transfer of activated CD4.sup.+ T.sub.H1, but not T.sub.H2 cells specific for encephalogenic epitopes. The major encephalogenic epitopes of myelin-derived sequences in EAE, such as MBP, can also activate human T cells of several different haplotypes including HLA-DR2. R. Martin, et al., J. Exp. Med. 173:19-24 (1992). The experimental disease is characterized by a relapsing-remitting course (R-EAE) of neurological dysfunction, perivascular mononuclear infiltration and demyelination. CNS damage is probably mediated by inflammatory cytokines which can activate additional monocytes and macrophages non-specifically. J. E. Blalock, The Immune System. Our Sixth Sense, The Immunologist, 2:8-15 (1994).
Although the initial attack in EAE can be induced by the administration of either T cells specific for MBP or for PLP, close examination of reactivities of T cells in the primary and subsequent relapses demonstrates the presence of T cells which interact with specificities other than the inducing epitopes. This expansion of encephalogenic epitopes is termed "determinant spreading". S. D. Miller and W. J. Karpus, Immunology Today 15:356-361 (1994), P. V. Lehman, T. Forsthuber, A. Miller, and E. E. Sercarz, Nature 358-155-157 (1992), H. Jiang, S-I. Zhang and B. Pernis, Science 256:1213-1215 (1992). Antigen specific treatment would therefore, be expected to be more effective when administered early in the course of the disease, before the onset of increasing epitope complexity and eventual non-specific inflammation.
The goal of immunologic therapy is to restore tolerance without suppressing the entire immune system which can lead to complications such as infection, hemorrhage, and cancer. Drugs currently used to treat autoimmune diseases are non-specific immunosuppressive agents, such as anti-inflammatory agents or drugs which can block cell proliferation or depress proinflammatory cytokines. In general, these agents are effective for limited duration and subject to devastating complications.
It is desirable to suppress the immune system in a more specific way to control the response to self-antigens and theoretically "cure" the disease without down-regulating the entire immune system. Several specific immunotherapies have been hypothesized and tested in recent years, many of which are impractical or do not work in humans. For example, high affinity peptides can be synthesized which interact with MHC class II molecules and prevent the binding of encephalogenic peptides, thereby preventing the activation of pathogenic T cells. A. Franco et al., The Immunologist 2:97-102 (1994). This approach is disadvantageous in that it is difficult to obtain effective concentrations of inhibitor peptides in vivo. G. Y. Ishioka et al., J. Immunol. 152:4310-4319. In an alternate strategy, peptides which are analogs of encephalogenic sequences have been shown to antagonize the T cell receptors of antigen-specific T cells, rendering them unreactive, although the exact mechanism is at present unknown. S. C. Jameson et al., J. Exp. Med 177:1541-1550 (1993), N. Karin et al., J. Exp. Med. 180:2227-2237 (1994), V. K. Kuchroo et al., J. Immunol. 153:3326-3336 (1994). Oral administration of myelin has been tested and found to induce a state of immunological unresponsiveness thought to be mediated by the induction of suppressor T cell or of anergy. H. L. Weiner et al., Annu. Rev. Immunol. 12:809-837 (1994), C. C. Whitacre et al., J. Immunol. 147:2155-2163 (1991), S. J. Khoury et al., J. Exp. Med. 176:1355-1364 (1992). This treatment has been found to be efficacious for some but not all individuals. H. L. Weiner et al., Science 259:1321-1324 (1993). Thus, it is evident that improvements are needed to treat MS and other autoimmune disorders with an effective, immunospecific approach.